A potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), exhibits unique properties that can be utilized to treat chronic pain conditions. TRPV1, a Ca2+ permeable, nonselective cation channel, is activated by physical and chemical stimuli and mediates inflammatory thermal sensation. Presently, this receptor is being considered as a target for analgesics through the evaluation of different antagonists. This proposal will evaluate an approach utilizing agonistic activity of RTX to inhibit nociceptive neurotransmission. In this proposal, using spinal cord slice preparation, we will test the hypothesis that in the short-term, administration of RTX inhibits synaptic transmission by activating presynaptic TRPV1 and causing a depolarization block, thus reducing nociceptive transmission. Then, using behavioral studies, we will test the hypothesis that in the long-term, intrathecal administration of RTX alleviates nociceptive inflammatory pain and the effect is likely to be due to ablation of TRPV1 expressing nerve terminals as a result of the excessive Ca2+ influx. The intrathecal administration of RTX selectively affects TRPV1 expressing nerve terminals of the sensory neurons at the spinal cord without affecting the dorsal root ganglion (DRG) neurons. Since TRPV1 expressing DRG neurons fulfill other efferent functions, the release of inflammatory and neuro/vasoactive substances can be preserved by the intact DRG. Preliminary/published results indicate that RTX causes a slow and sustained activation of TRPV1 leading to nerve terminal depolarization and depression of synaptic transmission. Further, intrathecal administration of RTX promotes a selective and localized ablation of TRPV1 expressing central terminals of sensory neurons at the injection site in the dorsal horn (DH), and leads to sustained pain relief in behavioral models. These studies will enhance our understanding of the role of central TRPV1 in nociceptive transmission. The selective action of RTX on TRPV1 containing nociceptive nerve terminals is a possible strategy to consider for treating chronic, debilitating and terminal pain conditions arising from large and inaccessible areas, due to malignancies of internal organs and bone. PUBLIC HEALTH RELEVANCE: Refractory chronic pain is a major problem especially in terminally ill patients. Treatment with morphine is currently the only available option, which causes significant side effects, ranging from sedation to respiratory depression leading to premature death. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1) exhibits unique properties that can be utilized to treat chronic pain conditions. Intrathecal administration of RTX potently and selectively activates TRPV1 causing a depolarization block of the central nerve terminals in the short-term, and ablating TRPV1 containing central nerve terminals of the sensory neuron in the long-term at the level of the spinal cord. Since RTX action is selective to the central nerve terminals, other neuronal functions can be preserved. These include the peripheral efferent functions of DRG neurons, such as the regulation of microvascular circulation by TRPV1-mediated release of inflammatory and neuro/vasoactive agents. Finally, preventing nociceptive transmission at the level of the spinal cord using RTX will be a useful strategy in chronic, debilitating and intractable pain arising from large and inaccessible areas, such as malignancies of internal organs and bone.